Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
  • C07H15/20—Carbocyclic rings
  • C07H15/24—Condensed ring systems having three or more rings
  • C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins

Definitions

• This invention relates to new fluorine-containing anthracycline derivatives which exhibit antitumor activities but are of low toxicities and in which the 3'-hydroxyl group and/or the 4'-hydroxyl group of the sugar moiety of anthracycline has or have been mono- or di-O-aminoalkanoylated.
• this invention relates to such new fluorine-containing anthracycline derivatives which are produced by esterifying with an amino acid the 3'-hydroxyl group and/or the 4'-hydroxyl group of 7-O-(2,6-dideoxy-2-fluoro- ⁇ -L-talopyranosyl) daunomycinone or -adriamycinone, or 7-O-(2,6-dideoxy-2,6,6,6-tetrafluoro- ⁇ -L-talopyranosyl)adriamycinone or 7-O-(2,6-dideoxy-6,6,6-trifluoro- ⁇ -L-lyxo-hexopyranosyl) adriamycinone, as the new anthracycline derivatives which have antitumor activities and are less toxic but are soluble in water.
• daunomycin As the antibiotics of the anthracycline type are known daunomycin (named also as daunorubicin) and adriamycin (named also as doxorubicin). Daunomycin and adriamycin have broad anticancer spectra against experimental tumors and have found wide-spread clinical utilities as chemotherapeutic anticancer or antitumor agents.
• daunomycin and adriamycin can exhibit somewhat strong anticancer or antitumor activities against various kinds of cancers or tumors but are not necessarily satisfactory as the anticancer agent or antitumor agent. Namely, daunomycin and adriamycin have been used widely as the chemotherapeutic antitumor agents for clinical treatments of tumor-bearing patients, but they are also known to bring about serious side-effects such as leukocytopenia, alopecia, myocardiopathy and others, in many instances.
• the present inventors succeeded in synthesizing such anthracycline derivatives having anticancer or antitumor activities and represented by the following general formula (A): wherein Q means a hydrogen atom or a hydroxyl group, for example, 7-O-(2,6-dideoxy-2-fluoro- ⁇ -L-talopyranosyl) daunomycinone and 7-O-(2,6-dideoxy-2-fluoro- ⁇ -L-talopyranosyl)adriamycinone (Japanese Patent No. 1905434; Japanese Patent Publication "Kokoku" No. Hei-6-31298 and European Patent No. 0230013).
• the present inventors also succeeded in synthesizing such antitumor anthracycline derivatives represented by the general formula (B): wherein G means a group -(CH 2 ) m H, where m is an integer of 1-6, or a group -(CH 2 ) n -COOH, where n is zero or an integer of 1-10 (Japanese Patent Publication "Kokoku” No. Hei-6-42304 and European Patent No. 0275431).
• the present inventors further had conducted different investigations in an attempt to synthesize newly such novel anthracycline derivatives which exhibit higher anticancer or antitumor activities and lower toxicities than those of daunomycin, adriamycin and the anthracycline derivatives of the above-mentioned formulae (A) and (B).
• anthracycline derivatives of the general formulae (A) and (B) above are remarkedly superior to those of daunomycin and adriamycin but are not yet satisfactory to a full extent. Accordingly, it is now still desirable to obtain such new anthracycline derivatives which can have much more enhanced anticancer or antitumor activities.
• the present inventors also have found that even when an anthracycline derivative having the general formula (C) is administered at low dosages into test animals, the anthracycline derivative so administered can display a high anticancer or anitumor activity (see the specifications of Japanese patent applications No. 67714/94 and PCT application No. PCT/JP95/00407 published under PCT international publication No. W095/24412 dated September 14, 1995).
• Examples of the daunomycinone or adriamycinone derivative of the general formula (C) above include the under-mentioned compouns (C-a) and (C-b).
• the present inventors also have found that even when an anthracycline derivative having the formula (D) is administered at low dosages to test animals, the anthracycline derivative so administered can display a high anticancer or antitumor activity, and that development of acute toxicity does not take place in the test animals having received the administration of the anthracycline derivative of the formula (D ) at the low dosages which can give high anticancer or antitumor effects in the test animals by the administration of said anthracycline derivative (see the specification of the aforesaid PCT application No. PCT/JP95/00407).
• anthracycline derivatives of the formulae (A), (B), (C) and (D) above can exhibit high antitumor activities, but all of them, except the compound of the formula (B), are poorly soluble in water, so that there occurs a problem that these anthracycline derivatives are difficult to be formulated into an injectable preparation of aqueous solution-type, when these anthracycline derivatives are to be administered as an injectable preparation.
• the present inventors had already succeeded in providing some water-soluble derivatives of an adriamycin-type compound such as the compounds of the above formula (B), by hemi-esterification of the 14-position of the adriamycin-type compound with a dicarboxylic acid.
• novel water-soluble derivatives can be produced from the fluorine-containing anthracycline derivatives of the formula (A), formula (C) or formula (D), when the present inventors employ another way of approach that an amino acid is introduced by an ester-linkage into either one or both of the 3-hydroxyl group and the 4-hydroxyl group of the sugar moiety of said fluorine-containing anthracycline derivatives, followed by making such salt-forming reaction that the amino group(s) present in the side-chain of the amino acid so introduced is or are converted into a salt with an inorganic acid or organic acid, and further that all of the above-mentioned water-soluble derivatives of the fluorine-containing anthracyclines so produced are able to maintain high antitumor or anticancer activities.
• a 7-O-(2,6-dideoxy-2-fluoro-3-O- or -4-O-or -3,4-di-O-aminoalkanoyl- ⁇ -L-talopyranosyl)anthracycline derivative represented by the general formula wherein Q is a hydrogen atom or a hydroxyl group, and at least one of A 1 and A 2 is or are (i) glycyl group or a substituted glycyl group having the following formula (a): where R is a hydrogen atom or an alkyl group of 1-8 carbon atoms, or an aryl group, particularly, phenyl group or a substituted phenyl group, or an aralkyl group, particularly a phenyl-(C 1 -C 6 ) alkyl group, or (ii) an ⁇ -amino acid residue having the following formula (b): -CO-B-NH 2 where B
• the anthracycline derivative of the general formula (I) according to the first aspect of this invention embraces new compounds of six classes (i) to (vi) as described below.
• the anthracycline derivative of the general formula (II) according to the second aspect of this invention embraces new compounds of six classes (i) to (vi) as described below.
• a 1 or A 2 in the compound of the general formula (I) according to the first aspect of this invention or in the compound of the general formula (II) according to the second aspect of this invention may be, for example, glycyl group or a substituted glycyl group which may be L-alanyl group, L-valyl group, L-leucyl group. L-isoleucyl group or L-phenylalanyl group.
• a 1 or A 2 in the compound of the general formula (I) or (II) above may be an ⁇ -amino acid residue of the formula -CO-B-NH 2 where B has the meanings as defined hereinbefore, when A 1 or A 2 may be, for example, 3-aminopropionyl group, 4-aminobutyryl group or 4-amino-2,2-dimethylbutyryl group.
• Examples of the pharmaceutically acceptable acid addition salt formed at the amino group(s) of the anthracycline derivative according to the first aspect or the second aspect of this invention includes the acid addition salts with a pharmaceutically acceptable inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid, or a pharmaceutically acceptable organic acid such as acetic acid, trifluoroacetic acid, propionic acid, malonic acid, lactic acid, tartaric acid or methanesulfonic acid.
• a pharmaceutically acceptable inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid
• a pharmaceutically acceptable organic acid such as acetic acid, trifluoroacetic acid, propionic acid, malonic acid, lactic acid, tartaric acid or methanesulfonic acid.
• anthracycline derivative of the general formula (I) according to the first aspect of this invention embraces the under-mentioned compounds as preferable particular examples of the derivative of the formula (I).
• the adriamycinone derivative of the general formula (II) according to the second aspect of this invention embraces the under-mentioned compounds as preferable particular examples of the derivatives of the formula (II).
• the compounds of the general formula (I) according to the first aspect of this invention have markedly high antitumor activities against experimental tumors in animals, and that the antitumor activities of the compounds of the formula (I) of this invention are comparable with or remarkably superior to the antitumor activities of daunomycin and adriamycin.
• Test Example 1 Some examples of tests are now described in Test Example 1 below to show the antitumor activities of several compounds which are embraced by the compounds of the general formula (I) according to this invention.
• CDF 1 mice four mice per group were intraperitoneally transplanted with cells of Leukemia L-1210 at an amount of 1 x 10 5 cells/mouse. Since an elapsed time of 24 hours from the transplantation of the leukemia cells, a test compound according to this invention was administered intraperitoneally to the mice under test for 9 consecutive days once per day. The mice so treated were observed for 60 days after the administration of the test compound. While, mice of the control group (the untreated group) were administered with only physiological saline after the transplantation of the L-1210 cells.
• mice in the treated group and in the control group were counted, and the mean survival days of mice in the treated group and in the control group were then calculated. From the mean survival day (C) of the untreated mice of the control group and the mean survival day (T) of the treated mice of the treated group, there were evaluated percentages (%) of the increase in the life-span of the treated mice, as T/C %.
• FT-DM 7-O-(2,6-dideoxy-2-fluoro- ⁇ -L-talopyranosyl)daunomycinone
• FT-ADM 7-O-(2,6-dideoxy-2-fluoro- ⁇ -L-talopyranosyl)adriamycinone
• mice of the control group was amounting to 8 to 9 days
• mean survival day of mice of the comparative groups having received the administration of adriamycin was varying dependently on the dosage of adriamycin.
• mice which could be cured by the administration of the test compound and survive for 60 days or longer were observed at a rate of at least one mouse among the four mice tested in a group.
• the compound of the general formula (I) according to the first aspect of this invention can exhibit such antitumor activities which are comparable to or have been enhanced remarkably much than those of the parent compounds, FT-DM and FT-ADM.
• test compounds there were chosen several test compounds. And, the test compounds so chosen were added at varying concentrations to mouse leukemia, P388 cells or adriamycin-resistant P388 cells (P388/ADR) which had been incubated in test tubes containing an appropriate culture medium. The incubation of the tumor cells were then continued for 72 hours from the addition of the test compound, and determination was made to evaluate such concentrations of the test compound which could inhibit the growth of the leukemia cells by 50% (namely, IC 50 , ng/ml). Adriamycin (as the hydrochloride) was used as a comparative compound and was tested in the same manner as above. The test results obtained are summarized in Table 2 below.
• Daunomycin or adriamycin employed as the comparative drug in Test Examples 1 ⁇ 2 above is a carcinostatic agent which is actually used in clinical treatments. Daunomycin or adriamycin is administered to men at doses in a range of from 0.4 mg/kg to 2 mg/kg depending on the types of cancers to be treated.
• daunomycin and adriamycin each exhibit the anticancer or antitumor effects such that the percentages (%) of increase in life-span (T/C, %) so obtained amount to about 138% to 171% and to approximately 330% at maximum, with being accompanied by development of toxicity.
• novel anthracycline derivatives having the general formula (I) and the formula (II) respectively according to the first aspect and the second aspect of this invention have excellent antitumor activities and have low toxicities.
• said novel anthracycline derivatives of this invention are very much useful as the antitumor drug which is practically usable in the clinical treatments of the patients, and they are expectable to be valuable for use in therapeutic treatments of various kinds of tumors, similarly to daunomycin or adriamycin.
• the compounds of the general formula (I) according to the first aspect of this invention, as well as the compound of the formula (II) according to the second aspect of this invention can be utilized usefully as therapeutic agents for tumors or cancers in the medicinal treatments of solid cancers, ascitic cancers and the like.
• composition characterized in that the composition comprises as an active ingredient an anthracycline derivative represented by the general formula (I) described hereinbefore, or an adriamycinone derivative represented by the formula (II) described hereinbefore, or an acid addition salt thereof, in combination with a pharmaceutically acceptable carrier.
• the compound of the general formula (I) or the formula (II) according to this invention may usually be administered by a parenteral route. It is also feasible to administer the compound of this invention orally after the compound is mixed with a pharmaceutically acceptable solid or liquid carrier which is conventionally used in the pharmaceutic field, followed by formulating the resultant mixture into various preparation forms such as powder, granules, tablets or syrups, or injectable solutions and suspensions.
• the compound of this invention may be administered to animals in the form of an injectable solution or suspension of the compound by intraperitoneal injection, subcutaneous injection, blood vessel injection, either intravenous or intra-arterial, or local injection and the like.
• the compound of this invention may be administered to humans also in the form of an injectable solution or suspension of the compound by blood vessel injection, either intravenous or intra-arterial, or local injection and the like.
• the compound of this invention may be administered continuously or intermittently at such dosages and to such an extent that the total dosage would not exceed a certain level as determined in view of results of animal tests and various circumstances.
• the administration of the compound of this invention should, of course, be effected by changing the dosages of the compound appropriately in accordance with the way of administration and the conditions of the patients or animals to be treated, such as age, body weight, sex, sensitivity, foods, administration time, administration route, drugs to be administered in combination and the seriousness of patients or disease, etc.
• the compound of this invention may be administered at a substantially same dose as that of daunomycin or adriamycin when the compound is used as an antitumor or anticancer agent.
• Optimum dosage and frequency of administration of the compound of this invention under certain specific conditions must be determined by medicinal experts through preliminary tests in view of the above-mentioned quideline. These requirements for administration are equally applied to the oral administration of the compound of this invention.
• a further aspect of this invention includes a use of a daunomycinone or adriamycinone derivative having the general formula (I) as defined hereinbefore, or an adriamycinone derivative having the general formula (II) as defined hereinbefore, or a pharmaceutically acceptable acid addition salt thereof, in the manufacture of a pharmaceutical composition, particularly an antitumor composition.
• the preparation of the compound of the general formula (I-1a) may be conducted by such a process which comprises dissolving in pyridine 7-O-(2,6-dideoxy-2-fluoro- ⁇ -L-talopyranosyl)daunomycinone (Compound A'; one of the compounds having the formula (A) defined hereinbefore) set forth in the specification of the Japanese patent publication "Kokoku” No. Hei-6-31298 or the European patent No.
• N-protected amino acid active ester e.g., N-succinimide ester
• N-succinimide ester that may be either (i) an N-protected glycine or other ⁇ -amino acid of the general formula where R has the meanings as defined hereinbefore and Boc denotes tert-butoxycarbonyl group as an amino-protecting group, or (ii) an N-protected ⁇ -amino acid of the general formula HOOC-B-NH-Boc where B and Boc have the meanings as defined hereinbefore, with the proportion of the N-protected amino acid as added being equimolar to or in a slight excess over the amount of said Compound A'; stirring the resultant mixture at an elevated temperature of e.g.
• the 3'-hydroxyl group of the starting Compound A' can preferentially be esterified with the N-protected amino acid of the formula (III) or formula (IV), thereby to produce a 7-O-[2,6-dideoxy-2-fluoro-3-O-(N-Boc-aminoalkanoyl)- ⁇ -L-talopyranosyl]daunomycinone having the general formula wherein A 1a is either N-Boc-glycyl group or other N-Boc- ⁇ -amino acid residue of the formula (a'): where R and Boc have the same meanings as defined above, or an N-Boc- ⁇ -amino acid residue of the formula (b'): -CO-B-NH-Boc where B and Boc have the same meanings as defined above.
• the esterification reaction solution containing the N-Boc-3'-ester of the formula (I-1a') and the N-Boc-4'-ester of the formula (I-1b') may be diluted with chloroform and the resulting diluted solution is extracted with an appropriate solvent for removal of unnecessary by-products therefrom, followed by concentrating the resultant solution in chloroform under reduced pressure to dryness, whereby one can recover a mixture of the compound of the formula (I-1a') and the compound of the formula (I-1b').
• the 3'-hydroxyl group of the starting Compound A' is at first selectively esterified with the active ester of the N-protected amino acid of the formula (III) or formula (IV) in accordance with the process of the above item (A), to produce the N-Boc-3'-ester of the general formula (I-1a') above, which is then subjected to such a method comprising isolating the said N-Boc-3'-ester of the formula (I-a') from the resultant reaction solution, dissolving the N-Boc-3'-ester in acetonitrile, adding silica gel to the resultant solution and refluxing the resulting mixture.
• the migration process occurs wherein the N-protected amino acid residue at the 3'-position of the compound of the formula (I-1a') migrates to the 4'-position, in the same way as explained in the above item (A). Consequently, a larger part of the N-Boc-3'-ester of the general formula (I-1a') can be converted into the N-Boc-4'-ester of the general formula (I-1b') above.
• the resulting reaction solution containing the above-mentioned two esters so produced may then be treated to recover a mixture of these two esters therefrom, followed by treating the recovered ester mixture with trifluoroacetic acid to eliminate the amino-protecting group, Boc, therefrom, whereby one may obtain a mixture of the 3'-ester of the formula (I-1a) and the 4'-ester of the formula (I-1b) each in the form of their trifluoroacetates.
• the compound of the formula (I-1c) may be produced by such a process which comprises reacting the starting Compound A' employed in the process explained in the above item (A), namely 7-O-(2,6-dideoxy-2-fluoro- ⁇ -L-talopyranosyl)daunomycinone in pyridine with the active ester of the N-protected amino acid of the formula (III) or formula (IV) in 2 molar proportions or in a slight excess over the amount of Compound A' to esterify both the 3'- and 4'-hydroxyl groups of the starting Compound A' and thereby to produce a 7-O-[2,6-dideoxy-2-fluoro-3,4-di-O-(N-Boc-aminoalkanoyl)- ⁇ -L-talopyranosyl] daunomycinone having the general formula wherein both of A 1a and A 2a each are either N-Boc-glycyl group or other N-Boc
• reaction of esterification of the starting Compound A' as well as the deprotecting reaction of eliminating the Boc group from the N-Boc-3'4'-diester compound of the formula (I-1c') may be carried out in the same manner as described in the foregoing item (A).
• the 3',4'-diester compound of the general formula (I-1c) can be produced also by means of such a process which comprises effecting at first the process described in the above item (A) so as to produce the N-Boc-3'-ester compound of the formula (I-1a') and the N-Boc-4'-ester compound of the formula (I-1b') in the form of a mixture of them; recovering this mixture from the reaction solution; dissolving this mixture in pyridine; reacting the N-Boc-3'- and -4'-esters in pyridine with the active ester of the N-protected amino acid of the formula (III) or formula (IV) added in an equimolar proportion to said esters to effect the esterification reaction; thereby producing the N-Boc-3',4'-diester compound of the general formula (I-1c') above; and then eliminating the Boc group from said N-Boc-3',4'-diester compound by treatment with trifluoroacetic acid.
• the compound of the formula (I-2a) may be produced by means of such a process which comprises firstly utilizing as a starting compound 7-O-(2,6-dideoxy-2-fluoro- ⁇ -L-talopyranosyl) adriamycinone (Compound A"; one of the compounds of the general formula (A) given hereinbefore); reacting Compound A" in N,N-dimethylformamide (DMF) with tert-butylchlorodimethylsilane in the presence of imidazole to tert-butyldimethylsilylate the primary hydroxyl group at the 14-position of said Compound A" for the purpose of protecting the 14-hydroxyl group and thereby to produce 14-O-tert-butyldimethylsilyl-7-O-(2,6-dideoxy-2-fluoro- ⁇ -L-talopyranosyl)adriamycinone having the formula wherein TBS denotes tert-butyldi
• the resulting esterification reaction solution containing both of the compound of the formula (I-2a') and the compound of the formula (I-2b') produced may be diluted with chloroform and the resultant diluted solution may be extracted with an appropriate solvent for removal of unnesessary by-products, followed by concentrating the chloroform solution obtained under reduced pressure to dryness, whereby one can recover a mixture of the compound of the formula (I-2a') and the compound of the formula (I-2b').
• a second process for preparing the compound of the formula (I-2b) is such a process which comprises esterifying the compound of the formula (V) with the N-protected amino acid as described in the above item (D) to produce the compound of the formula (I-2a'); then separating this compound (I-2a') from the reaction solution by an appropriate procedure; dissolving the compound of the formula (I-2a') so recovered into acetonitrile; refluxing the resulting acetonitrile solution in the presence of silica gel to effect the migration process so that the N-protected amino acid residue at the 3'-position of the compound of the formula (I-2a') will migrate to the 4'-position of said compound with forming the compound of the formula (I-2b'); then recovering a mixture of the compound of the formula (I-2b') and the non-transferred compound of the formula (I-2a') from the reaction solution as formed in said transfer reaction; treating said mixture recovered with trifluoroacetic acid to eliminate simultaneously the TBS group and Boc
• the compound of the formula (I-2c) may be produced by such a process which comprises producing the N,O-protected-3'-ester product of the general formula (I-2a') and the N,O-protected-4'-ester product of the general formula (I-2b') in the form of a mixture of them in accordance with the process described in the item (E) above; recovering said mixture from the reaction solution; then dissolving said mixture in pyridine; adding to the resulting pyridine solution the active ester of the N-protected amino acid of the formula (III) or formula (IV) in an equimolar proportion to the ester products of the formulae (I-2a') and (I-2b') to effect the esterification reaction; thereby producing a 14-O-TBS-7-O-[2,6-dideoxy-2-fluoro-3,4-di-O-(N-Boc-aminoalkanoyl)- ⁇ -L-talopyranosyl]adri
• the compound of the formula (I-2c) may be produced also by such other process which comprises reacting the 14-O-protected-adriamycinone derivative of the above formula (V) in pyridine directly with 2 molar proportions or a slightly excessive proportion of the active ester of the N-protected amino acid of the formula (III) or formula (IV); thereby producing the N,O-protected-3',4'-diester product of the general formula (I-2c') at once; and then treating the compound of the general formula (I-2c') with trifluoroacetic acid to effect simultaneous removal of the TBS group and Boc group therefrom, so that the compound of the general formula (I-2c) is produced in the form of its trifluoroacetate.
• the compound of the formula (II-1a) and the compound of the formula (II-1b) each may be produced by such a process which comprises utilizing as a starting compound 7-O-(2,6-dideoxy-2,6,6,6-tetrafluoro- ⁇ -L-talopyranosyl)adriamycinone of the formula (C-b) given hereinbefore (see the specification of the PCT application No.
• the compound of the formula (II-1c) may be produced by such a process which comprises utilizing the compound of the formula (VI) as a starting compound; subjecting this starting compound to the esterification and the process of migration of the 3-O-aminoalkanoyl substituent of the esterification product in the same manner as in the process described in the foregoing item (G) so as to produce the compound of the formula (II-1a') and the compound of the formula (II-1b'); then recovering a mixture of these two compounds from the resulting reaction solution; reacting the recovered mixture of these two compound again with the active ester of the N-protected amino acid of the formula (III) or formula (IV) in pyridine; thereby producing a 14-O-TBS-7-O-[2,6-dideoxy-2,6,6,6-tetrafluoro-3,4-di-O-(N-Boc-aminoalkanoyl)- ⁇ -L-talopyranosyl]adria
• the compounds of the formula (II-2a), the formula (II-2b) and the formula (II-2c), respectively, may be produced by means of such a process which comprises utilizing as a starting compound 7-O-(2,6-dideoxy-6,6,6-trifluoro- ⁇ -L-lyxo-hexopyranosyl)adriamycinone of the formula (D) given hereinbefore (see the specification of the PCT application No.
• Boc means tert-butoxycarbonyl group (the same is applied hereinafter).
• the reaction solution so obtained was diluted with chloroform and the diluted solution was washed successively with a 20% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution and water, then dried over anhydrous sodium sulfate and concentrated under a reduced pressure.
• the resulting residue was subjected to a silica gel column chromatography (developer: chloroform-acetone, 5:1) for the isolation and purification, to afford the titled Compound 1 where the 3'-hydroxyl group has been esterified with 3-tert-butoxycarbnylaminopropionyl group (89 mg, yield 62%).
• the resulting reaction solution was concentrated under a reduced pressure, toluene was added to the resulting residue and the mixture obtained was subjected repeatedly to the concentration procedure under a reduced pressure in the same manner as above for the removal of trifluoroacetic acid.
• the resulting residue was reprecipitated from methanol-ether, to afford a mixture of the titled Compounds 3 and 4 in the form of trifluoroacetates as a red solid (33 mg, yield 81%).
• the ratio of Compound 3 to 4 in the mixture was about 1:5 based on the 19 F-NMR spectrum.
• TBS means tert-butyldimethylsilyl group Si(CH 3 ) 2 C(CH 3 ) 3 (the same is applied hereinafter).
• the resulting reaction solution containing the titled Compound 5 thus produced was diluted with chloroform, washed successively with a 20% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution and water, then dried over anhydrous sodium sulfate and concentrated under a reduced pressure.
• the resulting residue was purified by a silica gel column chromatography (developer: chloroform-acetone, 3:1), to afford the titled Compound 5 as a red solid (126 mg, yield 82%).
• the reaction solution after adding water (0.05 ml) thereto, was stirred at room temperature for 5 hrs, diluted with chloroform, washed successively with a 20% potassium hydrogen sulfate solution, a saturated aqueous hydrogen carbonate solution and water, then dried over anhydrous sodium sulfate and concentrated under a reduced pressure.
• the resulting residue was purified by a silica gel column chromatography (developer: chloroform-acetone, 5:1), to afford a mixture of the titled Compounds 6a and 7a as a red solid (211 mg, yield 66%).
• the ratio of Compounds 6a to 7a was about 2.5:1 based on 19 F-NMR spectrum, i.e. Compound 6a was the main product.
• the reaction solution was filtered and the filtrate was concentrated under a reduced pressure to leave a residue and the residue was reprecipitated from chloroform-hexane to yield a mixture of the titled Compounds 6a and 7a (56 mg).
• the ratio of Compounds 6a to 7a was about 1:2 based on 19 F-NMR spectrum, i.e. Compound 7a was the major product to Compound 6a.
• Example 2 (2) The mixture of Compounds 6a and 7a at the ratio of about 1:2 obtained in Example 2 (2) (12 mg) was dissolved in anhydrous pyridine (0.2 ml), and to the solution was added N-[N-(tert-butoxycarbonyl)glycyloxy]succinimide (12 mg). The mixture was stirred at 60°C for 15 h to effect the esterification.
• the resulting reaction solution was diluted with chloroform, washed, successively, with a 20% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution and water, then dried over anhydrous sodium sulfate and concentrated under a reduced pressure.
• the residue obtained was subjected to a silica gel column chromatography two times (first developer: chloroform-acetone, 15:1; and second developer: dichloromethane-acetone, 10:1) to isolate and purify the desired product, affording the titled Compound 10a as a red solid (10 mg, yield 71%).
• reaction solution was concentrated under a reduced pressure to leave a residue.
• residue was subjected to such treatment repeatedly that toluene was added to the residue and the resulting mixture was concentrated under a reduced pressure for the purpose of removing the trifluoroacetic acid.
• the resulting residue was reprecipitated from methanol-ether, thus affording the titled compound in the form of trifluoroacetate salt as a red solid (20.8 mg, yield 95%).
• A means L-alanyl group.
• A' means N-Boc-L-alanyl group.
• the reaction solution after water (0.1 ml) was added thereto, was stirred at room temperature for 3 hrs and then post-treated as in Example 3 (1) to leave a residue, which was purified by a silica gel column chromatography (developer: benzene-acetone, 6:1), to afford the titled Compound 10b as a red solid (20 mg, yield 29%).
• the mixture of the starting Compounds 6b and 7b was recovered in a yield of 34% thereof.
• A means L-alanyl group.
• A' represents N-Boc-L-phenylalanyl group.
• reaction solution was post-treated as in Example 2 (2) and the resulting solid was purified by a silica gel column chromatography two times (first developer: chloroform-acetone, 3:1; and second developer: toluene-ethyl acetate, 2:1), thus yielding the titled Compound 6c as a red solid (31 mg, yield 88%).
• A represents L-phenylalanyl group.
• A' represents N-Boc-L-phenylalanyl group.
• A represents L-phenylalanyl group.
• A' represents N-Boc-L-valyl group.
• Example 2 (1) Compound 5 (37 mg) obtained in Example 2 (1) was dissolved in anhydrous pyridine (0.6 ml), and to the solution was added N-[N-(tert-butoxycarbonyl)-L-valyloxy]succinimide (50 mg). The resulting mixture was stirred at 60°C for 3 h. The reaction solution was post-treated as in Example 3 (2) and the residue obtained was purified by a silica gel column chromatography two times (first developer: chloroform-acetone, 10:1; and second developer: toluene-ethyl acetate, 2:1), to afford one of the titled Compounds, 6d, as a red solid (46 mg, yield 96%).
• A represents L-valyl group.
• A' represents N-Boc-L-valyl group.
• Example 8 (1) The mixture of Compounds 6d and 7d (about 2:1) (26 mg) as obtained in Example 8 (1) was dissolved in anhydrous pyridine (0.4 ml), and to the solution was added an active ester, N-[N-(tert-butoxycarbonyl)-L-valyloxy]succinimide (36 mg). The mixture so obtained was stirred at 60°C for 15 h. Then, a further amount (27 mg) of the active ester was added and the stirring was continued for further 16 h.
• reaction solution was post-treated as in Example 7 (1) and the residue obtained was purified by a silica gel column chromatography two times (first developer: toluene-ethyl acetate, 20:1; and second developer: chloroform-acetone, 15:1), affording the titled compound as a reddish orange solid (5.7 mg, yield 18%).
• A represents L-valyl group.
• A' represents N-Boc-L-leucyl group.
• Example 2 (1) Compound 5 (31 mg) obtained in Example 2 (1) was dissolved in anhydrous pyridine (0.5 ml), and to the solution was added N-[N-(tert-butoxycarbonyl)-L-leucyloxyl]succinimide (38 mg). The mixture obtained was stirred at room temperature for 15 h, and then at 60°C for 3 h. The reaction solution was post-treated as in Example 2 (2) and the residue obtained was purified by a silica gel column chromatography (developer: chloroform-acetone, 15:1), to afford a mixture of the titled Compounds 6e and 7e as a red solid (19 mg, yield 46%). Also, 43% of the starting material used was recovered. The ratio of Compounds 6e to 7e in the mixture was about 3.5:1 as determined by 19 H-NMR spectrum
• A represents L-leucyl group.
• A' represents N-Boc-L-leucyl group.
• Example 10 (1) The mixture of Compounds 6e and 7e (about 1:2.2) (17.5 mg) as obtained in Example 10 (1) was dissolved in anhydrous pyridine (0.25 ml), and to the solution was added an active ester, N-[N-(tert-butoxycarbonyl)-L-leucyloxy]sccinimide, (17.5 mg). The mixture obtained was stirred at 60°C for 3 h. Then, a further amount (15 mg) of the active ester was added to the mixture and the said mixture was stirred at 60°C for 15 h. Water (0.05 ml) was added to the reaction solution, which was then stirred at room temperature for 11 h and then post-treated as in Example 3 (1).
• an active ester N-[N-(tert-butoxycarbonyl)-L-leucyloxy]sccinimide
• A represents L-leucyl group.
• the reaction solution so obtained was diluted with chloroform, washed successively with a 20% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution and water, then dried over anhydrous sodium sulfate and concentrated under a reduced pressure.
• the residue obtained was purified by a shilica gel column chromatography (developer: chloroform-acetone, 4:1), giving the titled compound 12 whose 14-hydroxyl group was protected with TBS group, as a red solid (125 mg, yield 82%)
• the resultant reaction solution after adding a small amount of water, was stirred for 1 hour, diluted with chloroform, washed successively with a 20% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution and water, then dried over anhydrous sodium sulfate and concentrated under a reduced pressure.
• the residue obtained was purified by a silica gel column chromatography (developer: chloroform-acetone, 6:1), to yield the titled Compound 13 which has the 3'-hydroxyl group esterified with tert-butoxycabonylglycyl group, as a red solid (80 mg, yield 53%).
• the next step was to bring about the migration of the N-(tert-butoxycarbonyl)glycyl group at the 3'-position of Compound 13 to the 4'-position. That is, the red sloid of Compound 13 above was dissolved in anhydrous acetonitrile (4 ml), to the solution was added a silica gel (Wako Gel C-200) (800 mg). The mixture was refluxed for 18 hrs. The reaction solution was filtered and the filtrate was concentrated under a reduced pressure. The resulting residue was reprecipitated form chloroformhexane to give a red solid (76 mg). The solid is a mixture of the titled Compound 14 with Compound 13, i.e. 3'-O-protected glycyl ester (2:1).
• the reaction solution obtained was diluted with chloroform, washed successively with a 20% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution and water, then dried over anhydrous sodium sulfate and concentrated under a reduced pressure.
• the residue was subjected to a silica gel column chromatography two times (first developer: chloroform-acetone, 15:1; and second developer: dichloromethane-acetone, 10:1) for the purpose of purification.
• the titled Compound 17 having the 3'- and 4'- hydroxyl groups both esterified with the N-protected glycyl groups, as a red solid (50 mg, yield 71%).
• the reaction solution so obtained was post-treated as in Example 12 (2), to afford a mixture of Compounds 20 and 21 as a red solid (68 mg).
• the ratio of Compounds 20 to 21 was 1:3.
• Example 14 (2) The mixture of Compounds 20 and 21 (at the ratio of 1:3) (54 mg) as obtained in Example 14 (2) was dissolved in anhydrous pyridine (0.7 ml), and to the solution was added N-[N-(tert-butoxycarbonyl)glycyloxy] succinimide (46 mg). The resulting mixture was stirred at 60°C for 17 h to effect the esterification reaction. The reaction solution was post-treated as in Example 13 (1), to afford the titled Compound 24 as a red solid (48 mg, yield 76%).
• Example 12 Compound 12 (109 mg) obtained in Example 12 (1) was dissolved in anhydrous pyridine (1.6 ml), and to the solution was added N-[N-(tert-butoxycarbonyl)-L-alanyloxy]succinimide (129 mg). The resulting mixture was stirred at 60°C for 3 h. The reaction solution obtained was subjected to a post-treatment in the same manner as in Example 12 (2) and the residue obtained was purified by a silica gel column chromatography (developer; chloroform-acetone, 4:1), to afford a mixture of the titled Compounds 26 and 27 as a red solid (102 mg, yield 76%). A 19 F-NMR spectrum shows the ratio of Compounds 26 to 27 to be about 2:1.
• A means L-alanyl group.
• A' means N-Boc-L-alanyl group.
• A means L-alanyl group.
• A' represents N-Boc-L-phenylalanyl group.
• Example 12 Compound 12 (48 mg) obtained in Example 12 (1) was dissolved in anhydrous pyridine (0.8 ml), and to the solution was added N-[N-(tert-butoxycarbonyl)-L-phenylalanyloxy]succinimide (71 mg), and the mixture was stirred at 60°C for 3 h.
• reaction solution was post-treated as in Example 12 (2) and the resulting solid was purified by a silica gel column chromatography two times (first developer: chloroform-acetone, 4:1; and second developer: toluene-ethyl acetate, 3:1), thus yielding the titled Compound 32 as a red solid (53 mg, yield 82%).
• A represents L-phenylalanyl group.
• A' represents N-Boc-L-phenylalanyl group.
• A represents L-phenylalanyl group.
• A' represents N-Boc-L-alanyl group.
• Example 14 (1) Compound 19 (86 mg) obtained in Example 14 (1) was dissolved in anhydrous pyridine (1.4 ml), and to the solution was added N-[N-(tert-butoxycarbonyl)-L-alanyloxy]succinimide (104 mg). The resulting mixture was stirred at 60°C for 3 h.
• the reaction solution was post-treated as in Example 12 (2) and the residue obtained was purified by a silica gel column chromatography two times (first developer: chloroform-acetone, 4:1; and second developer: tolueneethyl-acetate, 3:1), to afford a mixture of the titled Compounds 38 and 39, as a red solid (83 mg, yield 78%).
• A represents L-alanyl group.
• A' represents N-Boc-L-alanyl group.
• A represents L-alanyl group.
• A' represents N-Boc-L-phenylalanyl group.
• Example 14 (1) Compound 19 (58 mg) obtained in Example 14 (1) was dissolved in anhydrous pyridine (0.9 ml) and to the solution was added N-[N-(tert-butoxycarbonyl)-L-phenylalanyloxy]succinimide (88 mg). The mixture obtained was stirred at room temperature for 3 h. The reaction solution was post-treated as in Example 12 (2) and the residue obtained was purified by a silica gel column chromatography twice (first developer: chloroform-acetone, 4:1; and second developer: toluene-ethyl acetate, 3:1) to afford the titled Compound 44 as a red solid (65 mg, yield 83%).
• A represents L-phenylalanyl group.
• A' represents N-Boc-L-phenylalanyl group.
• A represents L-phenylalanyl group.
• Step (1) A known compound, methyl ⁇ -D-lyxopyranoside[Compound 50] of the formula is reacted with diethylaminosulfur trifluoride [(C 2 H 5 ) 2 NSF 3 ] to fluorinate selectively only the 4-hydroxyl group of Compound 50, whereby one produces methyl 4-deoxy-4-fluoro- ⁇ -L-ribopyranoside [Compound 51] of the formula as a 4-deoxy-4-fluoro derivative of Compound 50, with accompanying reversion of the steric configuration of the starting compound.
• Step (2) The hydroxyl groups at the 2- and 3-positions of Compound 51 are benzylated by reaction with benzyl bromide, whereby one produces methyl 2,3-di-O-benzyl-4-deoxy-4-fluoro- ⁇ -L-ribopyranoside [Compound 52] of the formula
• Step (3) Compound 52 is hydrolyzed with acid to cleave the glycoside linkage at the 1-position of said compound, whereby one produces 2,3-di-O-benzyl-4-deoxy-4-fluoro-L-ribopyranose [Compound 53] of the formula
• Step (4) Compound 53 is reacted with 1,3-propanedithiol in the presence of boron trifluoride-ethyl ether to cleave the sugar ring of Compound 53, whereby one produces 2,3-di-O-benzyl-4-deoxy-4-fluoro-L-ribose trimethylene dithioacetal [Compound 54] of the formula as a straight-chain compound of the dithioacetal type.
• Step (5) The primary hydroxyl group of Compound 54 is acetylated with acetic anhydride to produce 5-O-acetyl-2,3-di-O-benzyl-4-deoxy-4-fluoro-L-ribose trimethylene dithioacetal [Compound 55] of the formula
• Step (6) Compound 55 is reacted with mercury perchlorate in aqueous tetrahydrofuran in the presence of calcium carbonate to cleave the dithioacetal ring of Compound 55, whereby one produces 5-O-acetyl-2,3-di-O-benzyl-4-deoxy-4-fluoro-aldehyde-L-ribose [Compound 56] of the formula as an aldehyde-type compound.
• Step (7) Compound 56 is then reacted with trifluoromethyltrimethylsilane in anhydrous tetrahydrofuran in the presence of tetrabutylammonium fluoride. Thereby, one produces 6-O-acetyl-3,4-di-O-benzyl-1,5-dideoxy-1,1,1,5-tetrafluoro-L-altritol [Compound 57] of the formula as an L-altritol derivative having a trifluoromethyl group incorporated therein and its 2-epimer [Compound 58] of the formula:
• Step (8) Compound 57 is treated with a methanolic solution of sodium methoxide to remove the acetyl group from Compound 57.
• a methanolic solution of sodium methoxide to remove the acetyl group from Compound 57.
• Step (9) Reactions of oxidizing selectively the primary hydroxyl group of Compound 59 and forming simultaneously the ring of a pyranose are then conducted.
• the 2- and 6-hydroxyl groups of Compound 59 are trimetylsilylated, followed by effecting Collin's oxidation of the resulting trimethylsilylated product.
• the primary trimethylsilyloxy group of the resulting trimethylsilylated product is subjected to selective oxidation to afford an aldehyde product.
• This aldehyde product is then hydrolyzed with acid to remove the remaining trimethylsilyl group and concurrently bring about the cyclization reaction, whereby one produces 3,4-di-O-benzyl-2,6-dideoxy-2,6,6,6-tetrafluoro- ⁇ -L-talopyranose [Compound 60] of the formula as a 2,6-dideoxy-2,6,6,6-tetrafluorotalopyranose derivative.
• Step (10) The 1-hydroxyl group of Compound 60 is then acetylated with acetic anhydride to produce 1-O-acetyl-3,4-di-O-benzyl-2,6-dideoxy-2,6,6,6-tetrafluoro- ⁇ -L-talopyranose [Compound 61] of the formula
• Step (11) The benzyl groups at the 3- and 4-positions of Compound 61 are removed therefrom by catalytic reduction to produce l-O-acetyl-2,6-dideoxy-2,6,6,6-tetrafluoro- ⁇ -L-talopyranose [Compound 62] of the formula
• Step (13) Compound 63 is reacted with iodotrimethylsilane [(CH 3 ) 3 SiI] in anhydrous toluene, whereby one produces 3,4-di-O-acetyl-2,6-dideoxy-2,6,6,6-tetrafluoro-L-talopyranosyl iodide [Compound 64] of the formula as a 1-iodo sugar.
• 7-O-(2,6-Dideoxy-2,6,6,6-tetrafluoro- ⁇ -L-talopyranosyl)adriamycinone of the aforesaid formula (C-b) may also be produced by such a method which comprises providing adriamycinone; protecting the 14-hydroxyl group of adriamycinone with tert-butyldimethylsilyl group (abbreviated as TBS) as an appropriate hydroxyl-protecting group; thereby preparing 14-O-tert-butyldimethylsilyladriamycinone; condensing the 7-hydroxyl group of the latter compound with the aforesaid Compound 40, namely 3,4-di-O-acetyl-2,6-dideoxy-2,6,6,6-tetrafluoro-L-talopyranosyl iodide; and then eliminating the remaining hydroxyl-protecting group (TBS) from the resultant condensation product
• a methanolic solution of sodium methoxide to remove the acetyl group from Compound 71.
• the 2- and 6-hydroxyl groups of Compound 73 are trimethylsilylated, followed by effecting Collin's oxidation of the resulting trimethylsilylated product.
• the primary trimethylsilyloxy group of the resulting trimethylsilylated product is subjected to selective oxidation to afford an aldehyde product.
• This aldehyde product is then hydrolyzed with acid to remove the remaining trimethylsilyl group and concurrently bring about the cyclization reaction, whereby one produces 3,4-di-O-benzyl-2,6-dideoxy-6,6,6-trifluoro-L-lyxohexopyranose [Compound 74] of the formula as a 2,6-dideoxy-6,6,6-trifluoro-L-lyxo-hexopyranose derivative.
• Compound 77 is subjected to a silica gel column chromatographey as developed with dichloromethane, Compound 77 can be isolated separately into the ⁇ -anomer [Compound (77-a)] and the ⁇ -anomer [Compound (77-b)].
• the adriamycinone derivative of the aforesaid formula (D) may also be prepared by such a method which comprises condensing the 7-hydroxyl group of the aforesaid 14-O-TBS-adriamycinone with the above Compound 78, namely 3,4-di-O-acetyl-2,6-dideoxy-6,6,6-trifluoro- ⁇ -L-lyxo-hexopyranosyl bromide in the same manner as described in the foregoing item (J), and then removing the hydroxyl-protecting TBS group from the resulting condensation product.
• Referential Example 1 and Referential Example 2 which illustrate the synthesis of the aforesaid 2,6-dideoxy-2,6,6,6-tetrafluoro- ⁇ -L-talopyranose derivatives and the synthesis of the aforesaid 2,6-dideoxy-6,6,6-trifluoro-L-lyxohexopyranose derivatives, respectively, as well as Referential Example 3 and referential Example 4 which illustrate the synthesis of the aforesaid new adriamycinone derivative of the formula (C-b) and the synthesis of the aforesaid new adriamycinone derivative of the formula (D), respectively.
• Bn denotes benzyl group
• Ac denotes acetyl group in the different formulae shown therein.
• Methyl ⁇ -D-lyxopyranoside (Compound 50) (see F.P. Phelps et. al, "Journal of American Chemical Society” Vol. 48, pp. 503-507, 1926) (8.27 g) was suspended in anhydrous dichloromethane (167 ml) and the suspension was cooled to -40°C. To the suspension was added diethyl aminosulfur trifluoride (26.8 ml), and then the reaction mixture was stirred at room temperature for 1 hour to conduct the fluorination reaction.
• the resulting reaction solution was cooled to -20°C, to which methanol (170 ml) was added and the resulting mixture was stirred at room temperature for 15 hours.
• the reaction solution was neutralized with addition of sodium hydrogen carbonate (105 g) and the insoluble matters was removed by filtration.
• the filtrate was concentrated under a reduced pressure and the residue so obtained was purified by a silica gel column chromatography (developer: chloroform-acetone, 7:1), affording the titled Compound 51 as a syrup (7.54 g, yield 90%).
• the reaction solution was poured into a 3% aqueous acetic acid solution (500 ml) and the resulting mixture was extracted with chloroform.
• the chloroform solution obtained was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution in order. Thereafter, the solution thus washed was dried over anhydrous sodium sulfate and concentrated under a reduced pressure.
• the resulting residue was purified by a silica gel column chromatography (developer: toluene-ethyl acetate, 30:1), affording the titled compound 52 as a syrup (12.61 g, yield 81%).
• the resulting reaction solution was poured into water (200 ml) containing sodium hydrogen carbonate (38 g), and the mixture thus obtained was extracted with chloroform. Then, the chloroform solution obtained was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution in order. The solution thus washed was dried over anhydrous sodium sulfate and the dried solution was concentrated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography (developer: hexane-ethyl acetate, 5:2), thus yielding the titled Compound 53 which was a mixture of ⁇ -anomer and ⁇ -anomer as a syrup (2.58 g, yield 88%).
• the reaction solution was diluted with chloroform, washed with a 5% aqueous sodium hydroxide solution and water in order and dried over anhydrous sodium sulfate. The solution thus dried was concentrated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography (developer: toluene-ethyl acetate, 12:1 ⁇ 4:1, by gradient method), thus giving the titled compound 54 as a syrup (3.92 g, yield 75%).
• the reaction solution was poured into water (250 ml) and the mixture was stirred for 1.5 h and then extracted with chloroform.
• the resulting chloroform solution was washed with a 20% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution and water in order. Then, the solution thus washed was dried over anhydrous sodium sulfate and concentrated under a reduced pressure, thereby yielding the titled Compound 55 as a syrup (2.64 g) which was a quantitative yield.
• the resulting reaction mixture was filtered to remove insoluble matters and the filtrate was diluted with dichloromethane.
• a saturated aqueous sodium hydrogen carbonate solution was added to the resulting dichloromethane solution and the mixture was vigorously shaked.
• the insoluble matters so deposited were removed by filtration. Thereafter, the filtrate was washed with a 10% aqueous potassium iodide solution and water in order, dried over anhydrous sodium sulfate and then concentrated under a reduced pressure, thus affording the titled Compound 56 as a syrup (1.92 g, yield 92%).
• the next step was to conduct the selective oxidation reaction of the 6-trimethylsilyloxy group.
• anhydrous chromic acid (1.29 g) was suspended in a mixture of anhydrous dichloromethane (36 ml) and anhydrous pyridine (2.2 ml) and the suspension was stirred at room temperature for 30 minutes.
• the reddish yellow liquid so obtained was cooled with ice.
• a dichloromethane solution (5 ml) of the above-mentioned syrup, and the mixture obtained was stirred under ice-cooling for 2 h.
• the resulting reaction mixture was filtered through a short column packed with silica gel. The column was washed with ethyl acetate and the eluate from the column was concentrated under a reduced pressure to give a syrup (0.68 g).
• the resulting syrup (0.68 g) was dissolved in a mixture (8 ml) of dioxane and water (9:1) containing 0.1 N hydrogen chloride. The resulting solution was allowed to stand at room temperature for 1.5 h to conduct the reaction. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, and the resulting mixture was extracted with dichloromethane. The dichloromethane solution so obtained was washed with water, dried over anhydrous sodium sulfate and then concentrated under a reduced pressure, affording the titled Compound 60 as a syrup (0.48 g, yield 64%).
• the reaction solution so obtained was diluted with toluene, washed with a 10% aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogen carbonate solution and water in order.
• the reaction solution so washed was dried over anhydrous sodium sulfate and concentrated under a reduced pressure.
• the residue obtained was purified by a flash silica gel column chromatography (developer: hexane-ethyl acetate, 6:1), to give the titled Compound 64 as a syrup (132 mg, yield 58%).
• the resulting reaction solution was poured into water (400 ml) containing sodium hydrogen carbonate (74 g), and the mixture obtained was extracted with chloroform.
• the chloroform solution thus obtained was washed with a saturated sodium hydrogen carbonate solution and water, successively, and then dried over anhydrous sodium sulfate and concentrated under a reduced pressure.
• the resulting residue was purified by a silica gel column chromatography (developer: toluene-acetone, 12:1).
• the titled Compound 67 was obtained in the form of a mixture of ⁇ -anomer and ⁇ -anomer as a syrup (3.78 g, yield 82%).
• the reaction solution was diluted with addition of dichloromethane (50 ml) and a saturated aqueous sodium hydrogen carbonate solution (20 ml), and the mixture obtained was filtered through Celite to remove insoluble matters to obtain the filtrate. The residue was further washed with dichloromethane three times (30 ml each) and the washings were combined with the filtrate above.
• reaction soution was concentrated under a reduced pressure and was diluted with chloroform, washed with water, dried over anhydrous sodium sulfate and concentrated under a reduced pressure.
• the resulting syrup was dissolved in an 80% aqueous acetic acid (4 ml) and the solution was allowed to stand at 50°C for 1.5 h so that the 2-trimethylsilyloxy group as formed during the above reaction was converted into hydroxyl group.
• the next step was to carry out the selective oxidation reaction of the 6-trimethylsilyloxy group of the trimethylsilylation product obtained as above.
• anhydrous chromic acid (1.82 g) suspended in a mixture of anhydrous dichloromethane (25 ml) and anhydrous pyridine (3 ml), and the resulting suspension was stirred at room temperature for 30 minutes.
• the resulting red liquid was cooled with ice, to which was added a dichloromethane solution (3.5 ml) of the syrupy trimethylsilylated product above.
• the mixture was stirred under ice-cooling for 40 minutes.
• the resulting reaction solution was diluted with ethyl acetate and filtered through a glass filter packed with silica gel to obtain the filtrate.
• the filter used was washed with ethyl acetate, and said filtrate and the washings were combined together and the mixture was concentrated under a reduced pressure.
• To the residue was added ethyl acetate, and the resulting insoluble matters were filtered and washed in the same manner as above.
• the resulting filtrate and washings were combined and the mixture was concentrated under a reduced pressure, thus yielding a syrup (1.83 g) which was an aldehyde.
• the next step was to remove the remaining trimethylsilyl group and also to effect the cyclization reaction.
• the syrup obtained as above (1.83 g) was dissolved in a mixture (18 ml) of dioxane-water (10:1) (18 ml) containing 0.1N hydrogen chloride.
• the resultant solution was allowed to stand at room temperature for 50 minutes to conduct the reaction.
• a saturated aqueous sodium hydrogen carbonate solution 60 ml
• the resulting dichloromethane solution was washed with water, dried over anhydrous sodium sulfate and concentrated under a reduced pressure, to afford the titled Compound 74 as a syrup (1.42 g, yield 98%).
• Compound 77 (the anomer mixture) as obtained in the item (11) above, i.e. 1,3,4-tri-O-acetyl-2,6-dideoxy-6,6,6-trifluoro-L-lyxo-hexopyranose (89 mg) was dissolved in a 30% hydrogen bromide-acetic acid solution (0.9 ml), and the solution obtained was allowed to stand at room temperature for 5 hrs. to conduct the bromination reaction.
• reaction solution was diluted with chloroform, then washed with water, a saturated aqueous sodium hydrogen carbonate solution and water, successively, and subsequently dried over anhydrous magnesium sulfate and concentrated under a reduced pressure, to yield the titled Compound 78 as a syrup (85 mg, yield 90%)
• the resulting reaction solution was diluted with chloroform, filtered with aid of Celite to afford the filtrate.
• the residue from the filtration was washed with chloroform.
• the above filtrate was combined with the washings, and the resulting mixture was washed successively with a 30% aqueous potassium iodide solution, a saturated sodium hydrogen carbonate solution and water.
• the solution so washed with water was dried over anhydrous sodium sulfate and concentrated under a reduced pressure.
• the residue thus obtained was subjected to a silica gel column chromatography (developer: toluene-acetone, 12:1) to separate and purify the desired compound.
• the titled Compound 79 was obtained as a red solid (107 mg, yield 52%).
• the resulting reaction solution after addition of a small piece of dry ice thereto, was concentrated under a reduced pressure.
• the residue was diluted with chloroform, washed with water, dried over anhydrous sodium sulfate and concentrated under a reduced pressure.
• the resulting residue was dissolved in a mixture of chloroform-methanol and the solution obtained was subjected to a reprecipitation with addition of hexane, to yield the deacetylated product (67 mg) as a red solid.
• the resulting reaction solution was diluted with chloroform, filterd with aid of Celite to give the filtrate.
• the residue from the filtration was washed with chloroform.
• the above filtrate and the washings were combined and the mixture was washed, successively, with a 30% aqueous potassium iodide solution, a saturated aqueous sodium hydrogen carbonate solution and water.
• the water-washed solution was dried over anhydrous sodium sulfate and concentrated under a reduced pressure.
• the residue so obtained was subjected twice to a silica gel column chromatography (The first developer: toluene-acetone, 10:1, and the second developer: chloroform-acetone, 30:1) to separate and purify the desired compound.
• the titled Compound 80 50 mg, yield 26%) and ⁇ -anomer thereof (49 mg, yield 25%) were obtained each as a red solid.
• Compound 80 as obtained in the item (1) above i.e. 7-O-(3,4-di-O-acetyl-2,6-dideoxy-6,6,6-trifluoro- ⁇ -L-lyxo-hexopyranosyl)-14-O-tert-butyldimethylsilyladriamycinone (40 mg) was suspended in anhydrous methanol (4 ml), and to the resulting suspension was added a 0.25 N methanolic solution of sodium methoxide (0.13 ml). The mixture obtained was stirred at room temperature for 2.5 h to effect the elimination of the acetyl group from Compound 80.
• the resulting reaction solution after a small piece of dry ice was added thereto, was concentrated under a reduced pressure.
• the residue obtained was diluted with chloroform, washed with water, dried over anhydrous sodium sulfate and then concentrated under a reduced pressure.
• the residue obtained was dissolved in a mixture of chloroform-methanol, and hexane was added to the solution to cause reprecipitation, so that the deacetylation product (27 mg) was obtained as a red solid.

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